Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells

J. R. Ciacci-Zanella, A. H. Merrill, E. Wang, C. Jones

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Abstract

Fusarium moniliforme is a widespread fungal pathogen which primarily infects corn, but can also infect rice or wheat. Fusarium moniliforme produce several mycotoxins, the most prominent of which is called fumonisin B1 (FB1). Epidemiological studies have indicated that ingestion of fumonisins correlates with a higher incidence of oesophageal cancer in Africa and China. Fumonisins also cause a neurodegenerative disease in horses, induce hepatic cancer in rats, are nephrotoxic in rats, or cause pulmonary oedema in swine. Structurally, fumonisins resemble sphingolipids and can alter sphingolipid biosynthesis, suggesting that sphingolipid alterations play a role in disease and carcinogenesis. Previous studies determined that FBI blocked cell-cycle progression in CV-I cells but not COS-7 cells. Herein, we have examined the effects that FBI treatment has on cell-cycle regulatory proteins. Our studies established that FB1 treatment of CV-1 cells, but not COS-7 cells, leads to dephosphorylation of the retinoblastoma (Rb) protein. Cyclin dependent kinase 2 (CDK2) activity was repressed five- to 10-fold and cyclin E protein levels were lower in CV-1 cells after fumonisin treatment. Two CDK inhibitors, Kip1 and Kip2, were induced within 3 hours after fumonisin treatment of CV-1 cells, suggesting these two proteins mediate cell-cycle arrest induced by FBI. This mycotoxin caused large increases in sphinganine within 3 hours after addition of FBI. As sphingoid bases are known to induce Rb phosphorylation, this increase in sphinganine might be the stimulus for the suppression of cyclin dependent kinase activities via Kip1 and Kip2. The ability of FBI to accumulate sphingosine or sphinganine and arrest the cell cycle in some cells but not others may play an important role in carcinogenesis or disease.

Original languageEnglish (US)
Pages (from-to)791-804
Number of pages14
JournalFood and Chemical Toxicology
Volume36
Issue number9-10
DOIs
Publication statusPublished - Sep 1 1998

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Keywords

  • Cyclin E.
  • Cyclin dependent kinase inhibitors
  • Fumonisin B
  • Sphingolipids

ASJC Scopus subject areas

  • Food Science
  • Toxicology

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